Located on an alluvial plain, the city was heavily damaged by powerful earthquakes in February 2023 and subsequent aftershocks, floods and fires.

The city was founded as Alexandria (Ἀλεξάνδρεια) to commemorate Alexander the Great's victory over the Persian Darius III at Issus (Cilicia) in (333 BC).

The settlement was so called having been founded by Alexander the Great in 333 BC to supersede Myriandus as the key to the Syrian Gates, about 37 km (23 miles) south of the scene of his victory at the Battle of Issus against the Persian King Darius III.

A memorial, a monument and a bronze statue for the victory were raised at the city, and Herodian writes that they were there even during his time, c. 200 AD.

[9] The importance of the place comes from its relation to the aforesaid Syrian Gates, the easiest approach to the open ground of Hatay Province and Aleppo.

[10] The bishopric of Alexandria Minor was a suffragan of Anazarbus, the capital and so also the ecclesiastical metropolis of the Roman province of Cilicia Secunda.

There was fighting here under the Ottoman Empire: in 1606 the army of General Kuyucu Murat Pasha suppressed the Jelali revolts.

The British Levant Company maintained an agency and factory here for 200 years, until 1825, in spite of high mortality among its employees[8] because of regional disease, some due to lack of sanitation systems.

He proposed a new railway be built to the east from Alexandretta, which would greatly reduce the time for reaching India from the UK.

The De Bunsen Committee (8 April – 30 June 1915), a British inter-departmental group which was set up to discuss the issue in greater detail, preferred Haifa for this purpose.

[15] The German field marshal, Hindenburg, later said that Perhaps not the whole course of the war, but certainly the fate of our Ottoman Ally, could have been settled out of hand, if England had secured a decision in that region, or even seriously attempted it.

Possession of the country south of the Tauras [mountains] would have been lost to Turkey at a blow if the English had succeeded in landing at Alexandretta.

[citation needed] Following the collapse of the Ottoman Empire at the end of the First World War, most of Hatay including İskenderun was occupied by French troops.

19th-century traveler Martin Hartmann put the population of Iskenderun at roughly 500 households with no entry on ethnicity.

İskenderun is featured in the film Indiana Jones and the Last Crusade as an important starting point for the Grail map.